U.S. patent application number 15/541568 was filed with the patent office on 2017-12-07 for improved process for the preparation of lurasidone and its intermediate.
This patent application is currently assigned to PIRAMAL ENTERPRISES LIMITED. The applicant listed for this patent is PIRAMAL ENTERPRISES LIMITED. Invention is credited to Milind GHARPURE, Dhileepkumar KRISHNMURTHY, Galge REVANAPPA, Shashi Kant TIWARI, Ganesh WAGH, Manikrao WARPE, Yogesh ZALTE.
Application Number | 20170349601 15/541568 |
Document ID | / |
Family ID | 56355582 |
Filed Date | 2017-12-07 |
United States Patent
Application |
20170349601 |
Kind Code |
A1 |
GHARPURE; Milind ; et
al. |
December 7, 2017 |
IMPROVED PROCESS FOR THE PREPARATION OF LURASIDONE AND ITS
INTERMEDIATE
Abstract
The present invention provides an improved process for
preparation of the substantially pure
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (referred to as compound-II), which
is useful as a key intermediate for the synthesis of lurasidone
((3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1ylme-
thyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione).
The process comprises reaction of the compound-III (as described
herein) with the compound-IV (as described herein) in the presence
of a solvent mixture selected from an alcohol and water; and a base
The improved process for the preparation of compound II provides
the product with total amount of unreacted compound-IV as impurity
in less than 0.06% and the product with HPLC purity as
.gtoreq.99.8%. The process further refers purification of
Lurasidone hydrochloride, wherein the product contains the residual
acetone <5000 ppm.
Inventors: |
GHARPURE; Milind; (Mumbai,
Maharashtra, IN) ; TIWARI; Shashi Kant; (Pune,
IN) ; WAGH; Ganesh; (Mumbai, Maharashtra, IN)
; REVANAPPA; Galge; (Mumbai, Maharashtra, IN) ;
WARPE; Manikrao; (Mumbai, Maharashtra, IN) ; ZALTE;
Yogesh; (Mumbai, Maharashtra, IN) ; KRISHNMURTHY;
Dhileepkumar; (Mumbai, Maharashtra, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PIRAMAL ENTERPRISES LIMITED |
Mumbai |
|
IN |
|
|
Assignee: |
PIRAMAL ENTERPRISES LIMITED
Mumbai
IN
|
Family ID: |
56355582 |
Appl. No.: |
15/541568 |
Filed: |
January 5, 2016 |
PCT Filed: |
January 5, 2016 |
PCT NO: |
PCT/IB2016/050030 |
371 Date: |
July 5, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 487/10 20130101;
A61P 25/18 20180101; C07D 417/12 20130101 |
International
Class: |
C07D 487/10 20060101
C07D487/10; C07D 417/12 20060101 C07D417/12 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 8, 2015 |
IN |
67/MUM/2015 |
Claims
1. A process for the preparation of
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (II) of the following formula,
##STR00014## comprising; reacting the compound-III of the following
formula; ##STR00015## with the compound-IV of the following
formula; ##STR00016## in a mixture of protic solvents and a
base.
2. The process according to claim 1, wherein the solvent mixture
consists of an organic solvent and water.
3. The process according to claim 1, wherein the solvent mixture
consists of an alcoholic solvent and water.
4. The process according to claim 1, wherein the solvent mixture
comprises alcoholic solvent and water, wherein the ratio of
alcoholic solvent to water ranges from 1:1 to 10:10 as v/v
(volume/volume)
5. The process according to claim 1, wherein the solvent mixture
comprises alcoholic solvent and water, wherein the ratio of
alcoholic solvent to water ranges from 1:1 to 10:5 as v/v
(volume/volume).
6. The process according to claim 1, wherein the solvent mixture
comprises isopropyl alcohol (IPA) and water, wherein the ratio of
IPA to water is 3:1 v/v (volume/volume).
7. The process according to claim 1, wherein the base is selected
from the group consisting of sodium carbonate, potassium carbonate,
sodium bicarbonate, cesium carbonate, calcium carbonate, sodium
hydroxide or potassium hydroxide.
8. The process according to claim 1, wherein the compound II is
obtained in a yield of about 85-90%.
9. The process according to claim 1, wherein the compound II is
obtained with a purity of at least 99% (HPLC).
10. The process according to claim 1, wherein the compound II
contains total amount of unreacted compound-IV as impurities in
less than 0.06%.
11. The process according to claim 1, wherein the compound II is
further converted to Lurasidone free base or a pharmaceutically
acceptable salt thereof.
12. A process for the purification of Lurasidone salt comprising;
(w) preparing a solvent mixture consisting of an organic solvent
and water; (x) adding the Lurasidone salt to the solvent mixture of
step (w); (y) heating the mixture of step (x); (z) cooling the
reaction mixture of step (y) and isolating the precipitated
product.
13. The process according to claim 12, wherein the organic solvent
in step (w) is selected from alcoholic solvent, halogenated
solvent, cyclic solvent, protic solvent, aromatic solvent, ketone,
ester, hydrocarbon, nitrile or ether.
14. The process according to claim 12, wherein the organic solvent
in step (w) is an alcoholic solvent selected from ethyl alcohol,
n-propyl alcohol, isopropyl alcohol (IPA), isobutyl alcohol or
methanol, or a mixture thereof.
15. The process according to claim 12, wherein the heating
temperature in step (y) ranges from 75.degree. C. to 90.degree.
C.
16. The process according to claim 12, wherein the cooling
temperature in step (z) ranges from 20.degree. C. to 35.degree.
C.
17. The process according to claim 12, wherein the product pure
Lurasidone salt contains the residual acetone less than 5000
ppm.
18. A process for the purification of Lurasidone hydrochloride
comprising; (i) preparing a solvent mixture of isopropyl alcohol
(IPA) and water; (ii) adding the Lurasidone hydrochloride to the
solvent mixture of step (i); (iii) heating the mixture of step (ii)
at temperature about 85.degree. C.; (iv) cooling the reaction
mixture of step (iii) at temperature about 20-30.degree. C.; and
(v) isolating the precipitated product.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to an improved process for the
preparation of
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (hereafter referred to as the
compound-II), which is useful as a key intermediate for the
synthesis of Lurasidone
((3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1ylme-
thyl]
cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione). The
process of the present invention further involves transformation of
a quaternary ammonium salt (the compound-II) to lurasidone
(referred to as the compound-I) and pharmaceutically acceptable
salts thereof.
BACKGROUND OF THE INVENTION
[0002] The following discussion of the prior art is intended to
present the invention in an appropriate technical context, and
allows its significance to be properly appreciated. Unless clearly
indicated to the contrary, reference to any prior art in this
specification should not be construed as an expressed or implied
admission that such art is widely known or forms part of common
general knowledge in the field.
[0003] Lurasidone (the Compound-I), is an atypical antipsychotic
used in the treatment of schizophrenia and bipolar disorders. The
drug is marketed as hydrochloride salt (the compound-I.HCl) by
Sunovion Pharms Inc. under the tradename "LATUDA", in the form of
oral tablets. Latuda.RTM. is indicated for the treatment of
patients with schizophrenia. Lurasidone hydrochloride has the
chemical name
((3aR,4S,7R,7aS)-2-[((1R,2R)-2-{[4-(1,2-benzisothiazol-3-yl)-piperazin-1--
yl]methyl}cyclohexyl)-methyl]hexahydro-1H-4,7-methanisoindol-1,3-dione
hydrochloride, and is structurally represented as follows:
##STR00001##
[0004] Lurasidone being an important antipsychotic agent, a number
of processes for its preparation as well as for its intermediates
are known in the art.
[0005] U.S. Pat. No. 5,532,372 describe a process for the synthesis
of Lurasidone, which is illustrated below in Scheme-I. In the
process, the compound, cyclohexane-1,2-diylbis(methylene)
dimethanesulfonate (referred to as the compound-III) is reacted
with 3-(1-piperazinyl-1,2-benzisothiazole (referred to as the
compound-IV) in acetonitrile, and in the presence of sodium
carbonate to provide corresponding quaternary ammonium salt as
4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piperazin]-1'-i-
um methanesulfonate (the compound-II). The compound-II is further
treated with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide in
xylene, in the presence of potassium carbonate and
dibenzo-18-crown-6-ether to provide lurasidone.
##STR00002##
[0006] US Published Patent Application 2011/0263848 describes a
process for the preparation of the quaternary ammonium salt (the
compound-II) which comprises reacting
4-(1,2-benzisothiazol-3-yl)piperazine with
(1R,2R)-1,2-bis(methanesulfonyloxymethyl)-cyclohexane in a solvent
such as toluene in the presence of a phosphate salt.
[0007] Indian Published Patent Application 2306/MUM/2014 ("the
IN'2306 Application") describes a process for the synthesis of
lurasidone and the intermediates thereof, comprising reacting (R,R)
trans 1,2-bis(methane sulphonyl methyl)cyclohexane with
3-(Piperazine-1-yl)benzo[d]isothiazole in presence of a mixture of
two or more polar aprotic solvents selected from acetonitrile,
N,N-dimethyl formamide (DMF) and/or N,N-dimethyl acetamide (DMAc),
and a base at reflux temperature to obtain the quaternary ammonium
salt (the compound II), which is then converted to lurasidone. The
IN'2306 application demonstrated preparation of the compound II
using the solvent combination such as acetonitrile-DMF and
acetonitrile-DMAc.
[0008] US Published Patent Application 2011/0263847 describes a
process for the preparation of the quaternary ammonium salt (the
compound-II) comprising reacting
4-(1,2-benzisothiazol-3-yl)piperazine with
(1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane in a solvent
such as toluene, wherein the piperazine compound is used in an
excess amount i.e. 1.8 to 15 moles with respect to
(1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane.
[0009] Chinese Published Patent Application 102731512 describes a
process for the preparation of the quaternary ammonium salt (the
compound-II) comprises reaction of
4-(1,2-benzisothiazol-3-yl)piperazine with
(1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane in a solvent
such as toluene in the presence of a phase transfer catalyst.
[0010] In addition to the afore discussed patent documents, there
are a number of patent documents that describe a process for the
preparation of the quaternary ammonium salt (the compound-II), the
key intermediate for the synthesis of lurasidone. For instance,
Published PCT application WO2012/131606 A1, Indian Published patent
application 217/MUM/2013, Chinese published patent applications
102863437, 103864774 and 102827157 describe a process for the
preparation of the quaternary ammonium salt (compound-II) comprises
reaction of 4-(1,2-benzisothiazol-3-yl)piperazine with
(1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane in a solvent
or a solvent mixture such as acetonitrile, acetonitrile:water
solvent mixture, toluene or DMF, in the presence of a base.
[0011] It is evident from the discussion of the processes for the
preparation of the quaternary ammonium salt (the compound-II),
described in the afore cited patent documents that the reported
processes primarily involve use of acetonitrile either as the
single solvent or in a mixture of solvents. Acetonitrile is a
relatively toxic, and not an environment friendly solvent. Due to
its toxic nature, it can cause adverse health effects also.
Acetonitrile is covered under Class 2 solvents i.e. solvents to be
limited, and residual solvent limit of acetonitrile is 410 ppm in a
drug substance as per the ICH (International Conference on
Harmonisation) guidelines for residual solvents. Moreover,
acetonitrile is a costlier solvent, which renders the process
costlier and hence, is not an industrially feasible solvent.
[0012] It is also evident from the discussion of the processes
described in afore cited patent documents that some of the reported
processes involve use of high boiling solvents such as toluene and
dimethylformamide as reaction solvent, which subsequently require
high reaction temperatures, and this in turn leads to tedious
workup procedures. In view of these drawbacks, there is a need to
develop an industrially viable commercial process for the
preparation of lurasidone and its intermediates; which is simple,
efficient and cost-effective process and provides the desired
compounds in improved yield and purity.
[0013] Inventors of the present invention have developed an
improved process that addresses the problems associated with the
processes reported in the prior art. The process of the present
invention does not involve use of any toxic and/or costly solvents.
Moreover, the process does not require additional purification
steps and critical workup procedure. Accordingly, the present
invention provides a process for the preparation of lurasidone and
its intermediates, which is simple, efficient, cost effective,
environmentally friendly and commercially scalable for large scale
operations.
SUMMARY OF THE INVENTION
[0014] In one aspect, the present invention relates to an improved
process for the preparation of
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (the compound-II), comprising
reacting the compound-III (as described herein) with the
compound-IV (as described herein) in a mixture of protic solvents;
in the presence of a base.
[0015] In one aspect, the present invention relates to an improved
process for the preparation of
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (the compound-II), comprising
reacting the compound-III (as described herein) with the
compound-IV (as described herein) in a mixture of protic solvents
consisting of an alcoholic solvent and water; in the presence of a
base.
[0016] According to another aspect of the present invention, there
is provided an improved process for the preparation of
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (the compound-II), wherein the said
compound II contains total amount of unreacted compound-IV as
impurities in less than 0.06%.
[0017] According to another aspect of the present invention, there
is provided an improved process for the preparation of
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (the compound-II), wherein the said
compound II has purity of .gtoreq.99%.
[0018] According to another aspect of the present invention, there
is provided an improved process for the preparation of
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (the compound-II), wherein the said
compound II is obtained in a yield of about 85-90%.
[0019] In another aspect, the present invention relates to an
improved process for the purification of Lurasidone and/or its
salt, comprising treatment with a solvent mixture of an organic
solvent and water.
[0020] In another aspect, the present invention relates to an
improved process for the purification of Lurasidone hydrochloride,
comprising treatment with an alcoholic solvent and water
mixture.
[0021] In another aspect, the present invention relates to an
improved process for the purification of Lurasidone hydrochloride,
wherein the product contains the residual acetone less than 5000
ppm.
DETAILED DESCRIPTION OF THE INVENTION
[0022] Accordingly, the present invention relates to an improved
process for the preparation of
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (the compound II) represented by the
following formula,
##STR00003##
comprising reacting the compound-III represented by the following
formula;
##STR00004##
with the compound-IV represented by the following formula;
##STR00005##
in a mixture of protic solvents; in the presence of a base to
obtain the compound II.
[0023] The compound-II obtained by the afore described process is
optionally, converted into lurasidone free base or a
pharmaceutically acceptable salt thereof.
[0024] Accordingly, there is provided an improved process for the
preparation of lurasidone or a pharmaceutically acceptable salt
thereof; comprising the steps of: [0025] (a) preparation of
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (the compound II) represented by the
following formula;
[0025] ##STR00006## [0026] by reacting the compound-III represented
by the following formula;
[0026] ##STR00007## [0027] with the compound-IV represented by the
following formula;
[0027] ##STR00008## [0028] in a mixture of protic solvents
consisting of an alcoholic solvent and water; in the presence of a
base to obtain the compound II; and [0029] (b) converting the
compound-II into lurasidone free base or a pharmaceutically
acceptable salt thereof.
[0030] In the context of the present invention, the term
"optionally" when used in reference to any element; including a
process step e.g. conversion of a compound; it is intended to mean
that the subject element is subsequently converted, or
alternatively, is not converted to a further compound. Both
alternatives are intended to be within the scope of the present
invention.
[0031] In the context of the present invention, the term "a mixture
of protic solvents" means that the mixture of protic solvents
consists of at least two solvents, or more solvents. All
alternatives are intended to be within the scope of the present
invention.
[0032] In an embodiment, the mixture of protic solvents consists of
an alcoholic solvent and water.
[0033] Accordingly, in an embodiment the present invention relates
to a process for the preparation of
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (the compound II) represented by the
following formula,
##STR00009##
comprising reacting the compound-III represented by the following
formula;
##STR00010##
with the compound-IV represented by the following formula;
##STR00011##
in the presence of a mixture of protic solvents consisting of an
alcoholic solvent and water; in the presence of a base to obtain
the compound II;
[0034] In an embodiment, the alcoholic solvent contained in the
mixture of protic solvents is selected from the group consisting of
ethyl alcohol, n-propyl alcohol, isopropyl alcohol, isobutyl
alcohol and methanol; or a mixture thereof.
[0035] In an embodiment, the alcoholic solvent is isopropyl alcohol
(IPA).
[0036] In an embodiment, the mixture of protic solvents consists of
isopropyl alcohol and water.
[0037] In an embodiment, the mixture of protic solvents comprises a
mixture of alcoholic solvent and water, wherein the ratio of
alcoholic solvent to water ranges from 1:1 to 10:10 as v/v
(volume/volume). Preferably, the ratio of the alcoholic solvent to
the water ranges from 1:1 to 10:5 as v/v (volume/volume).
[0038] In the context of the present invention, the term "ratio"
when used with respect to any element e.g. solvent; it is intended
to mean that the subject element consists of v/v (volume/volume)
ratio ranging from 1:1 to 10:10 of the alcohol to water. All the
possible permutation and combination alternatives of v/v ratio are
intended to be within the scope of the present invention.
[0039] In an embodiment, the mixture of protic solvents comprises
an alcoholic solvent and water in the v/v ratio of 3 v:1 v
(alcohol:water).
[0040] In an embodiment, the solvent mixture of protic solvents
comprises isopropyl alcohol (IPA) and water in the v/v ratio of 3
v:1 v (IPA:Water).
[0041] In an embodiment, the base is an inorganic base.
[0042] In an embodiment, the inorganic base is selected from the
group consisting of sodium carbonate, potassium carbonate, sodium
bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide
and potassium hydroxide.
[0043] In an embodiment, the inorganic base is sodium
carbonate.
[0044] In a specific embodiment, the process for the preparation of
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)
octahydrospiro[isoindole-2,1'-piperazin]-1'-ium methanesulfonate
(the compound-II) comprises the steps of: [0045] (1) dissolving the
compound III in an alcohol; [0046] (2) adding the compound IV to
the reaction mixture of step (1): [0047] (3) adding a base and
water to the reaction mixture of step (2); [0048] (4) stirring the
reaction mixture of the above step (3) at a temperature of about
85.degree. C.; [0049] (5) filtering the reaction mixture of the
above step (4) at room temperature and evaporating the solvent
under vacuum; and [0050] (6) isolating the precipitated product
(the compound-II) obtained in the step (5), and washing the
compound-II with a solvent at room temperature to obtain the pure
compound-II.
[0051] The process of the present invention as per the specific
embodiment described above is illustrated in the following
Scheme-II,
##STR00012## [0052] The process as described above further
comprises optionally, converting the pure compound-II into the
lurasidone free base or a pharmaceutically acceptable salt
thereof.
[0053] The alcohol used in the step-(1) of the above process (as
depicted in the Scheme II) is selected from the group consisting of
ethyl alcohol, n-propyl alcohol, isopropyl alcohol (IPA), isobutyl
alcohol and methanol, or a mixture thereof.
[0054] In an embodiment, the alcohol used in step-(1) of the above
process (as depicted in the Scheme II) is isopropyl alcohol
(IPA).
[0055] In an embodiment, the base used in the step-(3) of the above
process (as depicted in the Scheme II) is an inorganic base.
[0056] The inorganic base used in the step-(3) of the above process
(as depicted in the Scheme II) is selected from the group
consisting of sodium carbonate, potassium carbonate, sodium
bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide
and potassium hydroxide.
[0057] In an embodiment, the base used in the step (3) is sodium
carbonate.
[0058] In an embodiment, the quantity of water added in step (3) of
the above process (as depicted in the Scheme II) is in the v/v
ratio with respect to alcohol solvent ranging from 1:1 to 10:10 as
v/v (volume/volume).
[0059] In an embodiment, the quantity of water added in step (3) of
the above process (as depicted in the Scheme II) is in the v/v
ratio with respect to alcohol; and the ratio of alcohol to water is
3 v:1 v (Alcohol:Water).
[0060] In an embodiment, the quantity of water added in step (3) of
the above process (as depicted in the Scheme II) is in the v/v
ratio with respect to isopropyl alcohol (IPA); and the ratio of IPA
to water is 3 v:1 v (IPA:Water).
[0061] The term `temperature of about 85.degree. C.` referred to in
the step (4) of the above process (as depicted in the Scheme II)
can range from 80.degree. C. to 90.degree. C.
[0062] The term `room temperature` referred to in the step (5) and
step (6) of the above process (as depicted in the Scheme II) can
range from 25.degree. C. to 35.degree. C.
[0063] The term `isolating the precipitated product` referred to in
the step (6) corresponds to the steps involving filtration, washing
and drying.
[0064] The solvent used in the step-(6) of the above process (as
depicted in the Scheme II) for the washing of product is selected
from an alcohol such as ethyl alcohol, n-propyl alcohol, isopropyl
alcohol, isobutyl alcohol and methanol; an ether such as ethyl
ether or propyl ether; aromatic hydrocarbon solvents such as
toluene, benzene or xylene; and other solvents such as acetone,
methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, ethyl
acetate, dioxane, tetrahydrofuran, dimethylformamide, dimethyl
sulfoxide or dimethylacetamide.
[0065] The solvent used in the step-(6) of the above process (as
depicted in the Scheme II) for the washing of product is selected
from toluene or acetone.
[0066] The process of the present invention as illustrated in the
above Scheme-II comprises reaction of the compound III with
compound IV in the presence of an inorganic base selected from
sodium carbonate or potassium carbonate, in a mixture of an alcohol
such as isopropyl alcohol (IPA) and water as the solvent, wherein
the v/v ratio of isopropyl alcohol with respect to water is 3 v:1 v
(IPA:Water). The reaction mixture was heated to a temperature of
80-85.degree. C. for about 24 hours, and filtered at room
temperature. The filtrate was distilled out under reduced pressure
till visible solid appears. The solid product was washed with
toluene and subsequently using acetone. The precipitated product,
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (the compound-II) was isolated and
the said compound was obtained in a yield of about 85-90% and
purity of about .gtoreq.99% (HPLC).
[0067] The inventors studied the effect of solvent ratio over the
yield and purity of compound-II. The Table: 1 consolidates the
observations by keeping water as 1 v while varying the IPA
volume.
TABLE-US-00001 TABLE 1 Yield % HPLC purity (%) Volume of IPA Volume
of water compound-II compound II 3 v 1 v 90.0 99.79 4 v 1 v 84.0
99.52 5 v 1 v 85.0 99.43 6 v 1 v 88.0 97.09 7 v 1 v 79.0 99.82
[0068] The inventors also studied the effect of solvent ratio over
the yield and purity of compound-II. The Table: 2 consolidate the
observations by considering IPA as 3 v while varying the water
volume.
TABLE-US-00002 TABLE 2 Yield % HPLC purity (%) Volume of IPA Volume
of water compound-II compound II 3 v 0.5 v 53.8 63.23 3 v 1 v 90.0
99.79 3 v 2 v 87.0 99.7 3 v 3 v 67.29 99.67 3 v 4 v 66.24 99.33
[0069] The pure product, (3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)
octahydrospiro[isoindole-2,1'-piperazin]-1'-ium methanesulfonate
(the compound II) was further converted to lurasidone free base or
pharmaceutically acceptable salt thereof by a process known in the
art, for instance, the process described in U.S. Pat. No.
5,532,372; wherein (3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)
octahydrospiro[isoindole-2,1'-piperazin]-1'-ium methanesulfonate
(compound II) is reacted with
bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide.
[0070] It is evident from the processes reported in the prior art
that the purity of the desired product i.e. the compound-II was
about 56.40% (HPLC) with un-reacted compound-IV as impurities in an
amount of about 42.46%; whereas the process of the present
invention provided the pure desired product, the compound-II in a
yield of about 85-90%, purity of about .gtoreq.99% (HPLC) with
un-reacted compound-IV as impurities in less than 0.06%. This
amounts to a significant advantage over the processes reported in
the prior art.
[0071] In an embodiment, there is provided an improved process for
the preparation of
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (the compound-II), wherein the
compound II contains total amount of un-reacted compound-IV as
impurities in less than 0.06%.
[0072] In an embodiment, there is provided an improved process for
the preparation of
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (the compound-II), wherein the
compound-II has HPLC purity as .gtoreq.99%.
[0073] It is further evident from the processes reported in the
prior art that the isolation of the pure compound-II involves use
of high boiling solvents which subsequently includes high reaction
temperature and in turn leads to tedious workup procedures. Also,
the processes known in the art involved treatment of the crude
compound-II with a solvent and heating to 60-65.degree. C. for
several hours, whereas the process of the present invention
provided the pure desired product compound-II without harsh
purification steps.
[0074] In another embodiment, the present invention relates to an
improved process for the purification of Lurasidone and/or its
salt, comprising treatment with a solvent mixture of an organic
solvent and water.
[0075] In another embodiment, the present invention relates to an
improved process for the purification of Lurasidone hydrochloride,
comprising treatment with an alcoholic solvent and water
mixture.
[0076] In yet another embodiment, the present invention relates to
an improved process for the purification of Lurasidone
hydrochloride, wherein the product contains the residual acetone
<5000 ppm. In an embodiment, the present invention relates to a
process for the purification of Lurasidone salt comprising: [0077]
(w) preparing a solvent mixture consisting of an organic solvent
and water; [0078] (x) adding the Lurasidone salt to the solvent
mixture of step (w); [0079] (y) heating the mixture of step (x);
[0080] (z) cooling the reaction mixture of step (y) and isolating
the precipitated product.
[0081] In a specific embodiment, the process for purification of
Lurasidone salt comprises the steps of:
(i) adding an organic solvent to the water; (ii) adding Lurasidone
and/or its salt to the stirring solvent mixture of step (i); (iii)
stirring the reaction mixture of the above step (ii) at temperature
of about 85.degree. C.; (iv) cooling the reaction mixture of the
above step (iii) at temperature of about 20.degree. C. to
30.degree. C.; and (v) isolating the precipitated product.
[0082] The process of the present invention as per the specific
embodiment described above is illustrated in the following
Scheme-III,
##STR00013##
[0083] The organic solvent used in the step-(i) of the above
process (as depicted in the Scheme III) is selected from the group
consisting of alcoholic solvent, halogenated solvent, cyclic
solvent, protic solvent, aromatic solvent, ketone, ester,
hydrocarbon, nitrile or ether.
[0084] In an embodiment, the solvent used in the step-(i) of the
above process (as depicted in the Scheme III) is an alcoholic
solvent.
[0085] The alcoholic solvent used in the step-(i) of the above
process (as depicted in the Scheme III) is selected from the group
consisting of but not limited to ethyl alcohol, n-propyl alcohol,
isopropyl alcohol (IPA), isobutyl alcohol and methanol, or a
mixture thereof.
[0086] In an embodiment, the alcoholic solvent used in step-(i) of
the above process (as depicted in the Scheme III) is isopropyl
alcohol (IPA).
[0087] The term `temperature of about 85.degree. C.` referred to in
the step (iii) of the above process (as depicted in the Scheme III)
can range from 75.degree. C. to 90.degree. C.
[0088] The term `temperature of about 30.degree. C.` referred to in
the step (iv) of the above process (as depicted in the Scheme III)
can range from 20.degree. C. to 35.degree. C.
[0089] The term `isolating the precipitated product` referred to in
the step (v) corresponds to the steps involving filtration, washing
and drying.
[0090] The process of the present invention as illustrated in the
above Scheme-III comprises addition of Lurasidone hydrochloride to
the mixture of solvent (IPA:water). The reaction mixture was
stirred at temperature of about 85.degree. C. The reaction mixture
was cooled to 20-30.degree. C. The precipitated solid filtered as
Lurasidone hydrochloride was found to contain residual acetone
content <5000 ppm.
[0091] The Table: 3 consolidates the observations showing
effectively lowering the residual acetone content from Lurasidone
hydrochloride by the treatment with alcohol:water solvent
system.
TABLE-US-00003 TABLE 3 Residual Acetone (ppm) Residual Acetone
(ppm) After purification Compound Before purification (IPA: water
treatment) Lurasidone HCl 10683 2817 5769 2
[0092] In another aspect, the present invention relates to an
improved process for the purification of Lurasidone hydrochloride,
comprising treatment with an alcoholic solvent and water
mixture.
[0093] In another aspect, the present invention relates to an
improved process for the purification of Lurasidone hydrochloride,
wherein the product contains the residual acetone <5000 ppm.
[0094] Advantageously, the above identified elements of the process
of the instant invention effectively contribute to the reduction of
overall cost of the process.
[0095] The invention is further illustrated by the following
examples which are provided to be exemplary of the invention, and
do not limit the scope of the invention. While the present
invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those
skilled in the art and are intended to be included within the scope
of the present invention.
EXAMPLES
Example-1: Preparation of
(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piper-
azin]-1'-ium methanesulfonate (the compound II)
[0096] Charged 150.0 mL (3 v) of isopropyl alcohol (IPA) in a flask
followed by the addition of the compound-III (50.0 g),
3-(1-Piperazinyl)-1,2-Benzisothiazole (32.84 g), sodium carbonate
granular (10.79 g) and water 50 mL (1 v). The reaction mixture was
heated at a temperature of 82-85.degree. C. for 24 to 25 h. Cooled
the reaction mixture to room temperature, filtered on Buchner
funnel and the filtrate was collected.
[0097] The filtrate was evaporated under vacuum at 55-65.degree. C.
till visible solid appears in the reaction mass. The solid was
stirred in 75 mL of toluene at room temperature and the solid was
filtered. The wet cake was transferred to a flask and added 125 mL
of acetone to it; followed by stirring at room temperature. The
resulting solid was filtered to yield the pure title compound
(II).
[0098] Yield: 63.4 g (90%)
[0099] Purity (by HPLC): 99.79%
[0100] Unreacted compound-IV as impurity in 0.05%.
Example-2: Preparation of Lurasidone Free Base
[0101] Charged 150.0 mL of N,N-dimethylformamide (DMF) in a flask
followed by the addition of 50.0 g of the compound-II (as obtained
in the above example-1), 19.5 g
(3aR,4S,7R,7aS)-4,7-methano-1H-isoindole-1,3(2H)-dione and 19.5 g
of potassium carbonate. The reaction mixture was heated at a
temperature of about 125.degree. C. for 24 h. The reaction mixture
was cooled to room temperature and 400 mL of water was added to it.
The reaction mixture was stirred, and the precipitated product was
filtered. The wet cake was washed with IPA and Lurasidone free base
is obtained as the pure product. [Yield: 46.52 g (80%)]
Example-3: Purification of Lurasidone Hydrochloride
[0102] Charged water (200 ml) and IPA (200 ml) in flask followed by
the addition of Lurasidone hydrochloride (50 gm, residual acetone:
5769 ppm). The reaction mixture was heated at a temperature of
75-80.degree. C. for about 30 min. The reaction mixture was cooled
to 20-30.degree. C. and stirred for about 2 hours. The precipitated
solid was filtered and isolated as pure Lurasidone hydrochloride
(residual acetone: 2 ppm)
* * * * *